2. CONTENTS
INTRODUCTION
HISTORY
RATIONALE
GUIDELINES
CLASSIFICATION OF ANTIBIOTICS
MECHANISM OF ACTION,DRUG INTERACTION AND
ADVERSE EFFECTS OF ANTIBIOTICS IN PERIODONTAL
THERAPY
ANTIMICROBIAL DOSING PRINCIPLES
DURATION OF ANTIBIOTIC THERAPY
2
3. SYSTEMIC ANTIBIOTICS THERAPY IN PERIODONTAL PRACTISE
LOCAL DRUG DELIVERY SYSTEMS
COMPARISON OF LOCAL AND SYSTEMIC ANTIMICROBIAL
THERAPY
SELECTING ANTIMICROBIAL AGENTS ON THE BASIS OF
CLINICAL DIAGNOSIS
ANTIBIOTICS PROPHYLAXIS IN MEDICALLY COMPROMISED
PATIENTS
RESISTANCE OF ANTIBIOTICS TO PERIODONTAL PATHOGENS
FAILURES IN ANTIBIOTIC THERAPY
CONCLUSION
REFERENCES
3
4. INTRODUCTION
During the past two decades, dentists and
microbiologists have embraced periodontal antibiotic
therapy as a powerful adjunct to conventional
mechanical debridement for therapeutic management of
the periodontal diseases
Antibiotics, are defined as naturally occurring or
synthetic organic substances that, in low concentrations,
inhibit or kill selective microorganisms
4
5. The concept of antibiotic periodontal therapy centers
upon the pathogenic microbiota, the patient, and the
drug
5
6. Antibiotics are a naturally occurring, semisynthetic or synthetic
type of antimicrobial agent that destroys or inhibits the growth
of selective microorganisms, generally at low concentrations.
The term was originally applied to substances extracted from
fungus or other living organisms, but today, also includes
synthetic products.
Antibiotics are drugs that can kill or stop the multiplication of
bacterial cells, at concentrations that are relatively harmless to
host tissues, and therefore can be used to treat infections caused
by bacteria.
Antibiotics do not remove calculus and bacterial residues, and
this is traditionally perceived to be an essential part of
periodontal therapy.
6
7. HISTORY
Inorganic arsenic compounds (proving true the old saying “
some remedies are worse than the disease”).
Synthetic dye was prontosil – converted in the human body to
sulfonamide
The greatest discovery in the era of antibiotics was Fleming’s
finding of Penicillium notatum producing a substance
(“penicillins”) that inhibited the growth of Staphylococcus
aureus
Adverse reactions of antibiotics- drug resistance, toxicity and
hypersensitivity reactions and interactions with other
medications.
7
8. The choice of antibiotics was initially based on empirical
evidence and included mainly penicillins.
1970’s
Tetracycline- HCl Controlled clinical studies on the
broad spectrum antimicrobial effectiveness of periodontal antibiotic
activity and low therapies were initiated
toxicity.
In the last decade, increased knowledge of the composition of
the periodontal microbiota has led to the development of
microbiological guidelines for selecting antibiotics.
8
9. RATIONALE OF ANTIBIOTIC THERAPY
Mechanical and surgical treatment combined with proper
oral hygiene measures can arrest or prevent further
periodontal attachment loss in most individuals by reducing
total supra-subgingival bacterial mass.
Individuals continue to experience periodontal breakdown,
may be due to the ability of major periodontal pathogens
like P.gingivalis, Aggregatibacteractinomycetemcomitans,
Fusobacteriumnucleatum, Treponemadenticola, bacteroids,
to invade periodontal tissues or to reside in furcations or
other tooth structures outside the reach of periodontal
instruments, or due to poor host defense mechanisms
9
10. Systemic periodontal antibiotic therapy aims to
reinforce mechanical periodontal treatment and to
support the host defense system in overcoming the
infection by killing subgingival pathogens that remain
after conventional mechanical periodontal therapy.
The susceptibility of bacteria to antibiotics may be the
key to the efficacy of systemic antibiotics in the
treatment of periodontal diseases.
10
11. Few chemotherapeutic agents can also reduce collagen
and bone destruction through their ability to inhibit
the enzyme collagenase.
Patients with gingivitis or stable adult periodontitis
usually respond well to mechanical periodontal therapy
and derive little or no additional benefit from antibiotic
therapy
11
12. GUIDELINES FOR USE OF ANTIBIOTICS IN PERIODONTAL
DISEASE
1. The clinical diagnosis and situation dictate the need
for possible antibiotic therapy as an adjunct in
controlling active periodontal disease as the patient's
diagnosis can change overtime.
2.Continuing disease activity is an indication for
periodontal intervention and possible microbial analysis
through plaque sampling.
12
13. 3.When used to treat periodontal disease, antibiotics are
selected based on the patient's medical and dental status,
current medications, and results of microbial analysis, if
performed.
4. Microbial samples may be obtained from individual
pockets with recent disease activity or from pooled
subgingival sites. A pooled subgingival sample may
provide a good representation of the range of periodontal
pathogens to be targeted for antibiotic therapy.
13
14. 5.Plaque sampling can be performed at the initial
examination, root planing, reevaluation, or supportive
periodontal therapy appointment.
6. Antibiotics have also been shown to have value in
reducing the need for periodontal surgery in patients
with chronic periodontitis.
7. Systemic antibiotic therapy should be an adjunct to a
comprehensive periodontal treatment plan. An
antibiotic strength 500 times greater than the systemic
therapeutic dose may be required to be effective against
the bacteria arranged in the biofilms.
14
15. 8. Slots et al. described a series of steps using
antiinfective agents for enhancing regenerative healing.
They recommend starting antibiotics :
12 days before surgery and continuing for a total of atleast
8 days, however, the value of this regimen has not been
well documented.
9. Haffajee et al.concluded that data support similar
effects for most antibiotics. Risks and benefits concerning
antibiotics as adjuncts to periodontal therapy must be
discussed with the patient before the antibiotics are used.
15
16. CLASSIFICATION OF ANTIBIOTICS
I Based on chemical structure
Sulfonamides and related drugs :
Sulfa diazine and others, sulfones Dapsone (DDS),
Para amino salicylic acid (PAS).
Diaminopyrimidines:
Trimethoprim, pyrimethamine.
β lactam antibiotics:
Penicillins, cephalosporins, monobactams,
carbapenems.
Tetra cyclines :
Oxytetracycline, doxycline etc
Nitro benzene derivative:
chloramphenical
16
24. MECHANISM OF ACTION, DRUG INTERACTION AND ADVERSE
EFFECTS OF ANTIBIOTICS USED IN PERIODONTAL THERAPY
24
For the purpose of organization, different classes of
antibiotics have been divided into categories based on their
bactericidal or bacteriostatic effect on various structures or
macromolecules associated with the bacterial cell. These
include:
Inhibition of cell wall synthesis (penicillins and
cephalosporins)
Inhibition of protein synthesis (tetracyclines, macrolides
and clindamycin); and
Interference with nucleic acid synthesis (metronidazole
and quinolones).
25. Evidence - penicillins and cephalosporins interfere with
transpeptidation
Chemical groupings around the β-lactam ring
Binding of the β -lactam antibiotic inactivates the
transpeptidase reaction
Formation of new peptidoglycan chains
Cross-linked and lack tensile strength
Weak points cell rupture due to osmotic lysis.
25
27. ADVERSE REACTIONS
Any foreign substance taken into the body can produce an
adverse reaction.
Two types :
i)Allergic hypersenstivity - common
ii)Direct toxicity – rare
Actual incidence of penicillin allergies is unknown
0.6 -10% of patients
Maculopapular rash, urticaria rash, fever, bronchospasm,
vasculitis, serum sickness, exfoliative dermatitis and anaphylaxis
27
28. Mild reactions: rash or skin lesions located on or about the
head and neck that may be accompanied by facial swelling
More severe reactions - involve the joints and result in
pronounced swelling and/or tenderness
Highly sensitized - anaphylaxis may occur and can result in
death.
More severe reactions - intravenous administration
If treatment with a penicillin is considered essential, skin
sensitivity testing should be done.
28
29. Drug interactions:
Although concurrent therapy involving the administration of an
aminoglycoside with a penicillin is often used for serious
infections, the two drugs should not be mixed together in vivo
since the penicillin may inactivate the aminoglycoside
Concurrent administration of allopurinol, a drug for the control
of elevated uric acid levels, with either an ampicillin or
amoxicillin antibiotic substantially increases the incidence of
rashes in patients receiving both drugs relative to those who
receive either alone.
29
30. CEPHALOSPORINS
Similar in action and structure to the penicillins.
Contain a nucleus consisting of a β -lactam ring fused to a 6-membered
dihydrothiazine ring
Confers resistance to the action of a number of β -lactamases normally
active against penicillins
30
31. All cephalosporin antibiotics are semisynthetic compounds
derived from cephalosporin C, a fermentation product of the
mold Cephalosporium acremonium
Cephalosporins are classified into four generations
First generation cephalexin , Cephatrizine
Active against both penicillin-sensitive and resistant
staphylococci, Neisseria and most Escherichia coli, Salmonella
and Proteus mirabilis strains
The drug is rapidly eliminated and only maintains adequate
blood levels for approximately 4 hours
Administration is difficult since it is not absorbed orally;
intramuscular injections are painful, and intravenous
administration may result in phlebitis
31
32. The first orally active cephalosporin approved for medical
use was cephaloglycin.
Cephalexin is more stable and has better oral absorption. It
is often used as follow-up therapy and for the treatment of
minor infections involving gram-positive organisms.
Cephatrizine has a similar gram-positive spectrum as
cephalexin but is more active against gram-negative
organisms.
Often cause intestinal distress following oral dosage and
are subject to hydrolysis by cephalosporinase β-lactamases.
32
33. SECOND GENERATION
cefuroxime and cefamandole
Good activity against gram-positive species and are more active than
the first generation compounds against E. coli, Proteus, Enterobacter
and P.mirabilis.
THIRD GENERATION - cefoperazone , cefotaxime
Stable to most β-lactamases
Often very active against difficult to treat gram-negative strains but are
less active against gram-positives such as staphylococci and
streptococci.
They are not absorbed well following oral administration and are only
available for intramuscular or intravenous administration
33
34. ADVERSE REACTIONS
Incidence of allergic reactions is almost as high as
pencillins
Patients allergic to penicillin may not be allergic to
cephalosporins
Adverse side effects include development of rashes,
urticaria, fever, gastrointestinal disorders ranging from
mild diarrhoea to pseudo-membranous colitis,
neutropenia and superinfections
34
35. AMINOGLYCOSIDES
Streptomycin, gentamicin, tobamycin, sisomicin, kanamycin,
amikasin, paromomycin, framycetin and neomycin.
Their main antibacterial spectrum is against gram negative bacilli
Exhibit variable degrees of activity against tubercular bacteria, some
are active against staphylococci, but most gram-positive and most
anaerobic bacteria are resistant
MECHANISM OF ACTION
Binding irreversibly to a particular protein or proteins of the 30s
ribosomal subunit to interfere with protein synthesis
Ability to cause detachment of the ribosomal complex from the mRNA
35
36. ADVERSE REACTIONS
Ototoxicity and nephrotoxicity have been frequently associated with
use of the aminoglycosides with an incidence rate of 2-10%.
May produce deafness due to their effect on the eighth cranial nerve
DRUG INTERACTION
Synergistic effect with other antibiotics, aminoglycosides are usually
given in lower doses in combination with other drugs
Penicillin and gentamicin are commonly used together for the
treatment of bacterial endocarditis
Parenteral administration , some are available as creams or ointments
for topical application.
36
37. TETRACYCLINE
Broad-spectrum antibiotics - Gram-positive
Gram Negative Bacteria
Mycoplasma,
Rickettsia
Chlamydia Infections
All tetracycline compounds consist of four fused cyclic rings, hence the
name tetracyclines
Tetracycline, doxycycline and minocycline are commonly used
Bacteriostatic and bacteriocidal at high concentrations
All three have a similar spectrum of activity, and resistance to one may
indicate resistance to all three. 37
38. CLASSIFICATION OF TETRACYCLINE
GROUP I
Tetracycline
Oxytetracycline
Group II
Demeclocycline
Group III
Doxycycline
minocycline
38
39. Mechanism of action
The drugs bind principally to the 30s ribosomal subunit and
specifically inhibit the binding of aminoacyl-t-RNA to the ribosomal
acceptor site
In high concentrations, they may cause alterations in the cytoplasmic
membrane, which results in leakage of nucleotides and other
compounds from the cell.
This action probably accounts for the rapid inhibition of DNA
replication, which occurs at the site of the membrane
Beneficial effect in the treatment of a number of dental-related
infections
Subacute bacterial endocarditis
Adjunct to conventional periodontal therapy
Treatment of acute necrotizing ulcerative gingivitis
Treatment of dental abscesses
39
40. Tetracycline and doxycycline have been shown to achieve
levels in the gingival fluid that are 2-4 times higher than
blood levels.
Minocycline, a more lipophilic compound, may yield
gingival fluid levels 5 times blood levels.
The ability of the tetracyclines to penetrate into the tissues
may explain the efficacy obtained in treating localized
aggressive periodontitis
Nonantimicrobial benefits
Inhibition of collagenase activity
Enhancement of reattachment or regeneration
40
41. CHEMICALLY MODIFIED TETRACYCLINE
To identify the site of the anticollagenase property, Golub and co-workers
1991, synthesized 10 different analogs of tetracyclines known as chemically-
modified tetracyclines (CMTs 1-10).
All 10 analogs lacked antimicrobial efficacy and inhibited collagenase
activity, but only 1 did not.
ADVANTAGES
The recent observations in rats shown that CMT-1 is absorbed after oral
administration more rapidly and has a longer serum half life than
tetracycline.
Their long-term systemic administration does not result in
gastrointestinal toxicity,
No resistance.
Can be used for prolonged periods.
41
42. ADVERSE REACTIONS
Nausea, heartburn, epigastric pain, vomiting and diarrhoea are more
common with tetracyclines
Diarrhoea is mainly due to the direct chemical irritation of the bowel by
unabsorbed drug
Induce changes in the intestinal flora and have been reported to be associated
with pseudomembranous colitis.
Superinfections of the intestines involving Candida albicans
Photosensitivity in sunny climates and greater skin sensitivity to the effects
of the sun
All tetracyclines are deposited in calcifying areas of the bones and teeth and
may cause a yellow discoloration.
Not given to children under the age of 8 years old because of the tendency to
permanently discolor developing teeth
42
43. Minocycline has been reported to cause dizziness, vertigo and tinnitus,
associated with prolonged high dosage and is more common in women.
Hypersensitivity reactions rare with tetracyclines.
Nephrotoxicity, mild leukopenia, neurotoxicity and possibly decreased
phagocytic activity
CONTRAINDICATIONS
Tetracyclines are contraindicated during pregnancy since these drugs cross
the placenta and can have toxic effects on the developing fetus
Drugs should not be given to nursing mothers since they are excreted in
human milk.
Avoided in patients on diuretics – blood urea may rise
Donot mix injectable tetracycline with pencillin – inactivation may occur
43
44. DRUG INTERACTIONS
Oral contraceptives less effective and may induce breakthrough bleeding.
Absorption of the tetracyclines from the stomach is impaired by divalent
cations due to binding by the tetracycline- should be avoided during
tetracycline therapy:
antiacids containing aluminum, calcium or magnesium;
dairy products such as milk, cheeses, etc.
that contain calcium; iron-containing preparations
Any bacteriostatic antibiotic may infer with the bactericidal action of
penicillins, tetracycline class drugs should not be used.
Tetracyclines proven to depress plasma prothrombin activity, patients on
anticoagulant therapy (coumarin, heparin, protoamine, etc.) may require
downward adjustment of the anticoagulant drug.
Concurrent use of tetracyclines and anesthetic, methoxyflurane, is
contraindicated since the combination has been reported to result in fatal
renal toxicity
44
45. MACROLIDES
Group of antibiotics that have in common macrocyclic lactone rings linked
with amino sugars
Approximately 40 different compounds, apart from erythromycin, only
spiramycin, oleandomycin, josamycin and rosaramicin have been used
clinically.
Erythromycin has generally been the most effective and is widely used as an
alternative to the B-lactam antibiotics for the treatment and prevention of
infections caused by gram-positive organisms.
In recent years new macrolide been derived from the macrolides derivatives
generally appear superior to erythromycin in that they offer
Better pharmacokinetic properties,
Excellent tissue distribution,
A longer therapeutic half-life and
Good activity against many gram-negative anaerobes
Azithromycin has received the most extensive use.
45
46. ERYTHROMYCIN
Wide range of activity against both gram-positive facultative and
anaerobic bacteria.
Eubacterium, Propionibacterium, Lactobacillus and Peptostreptococcus
species.
Most strains of Peptococcus are sensitive, as are the Actinomyces.
The causative agents of human actinomycosis, Actinomyces israelii and
Arachnia propionica, are both sensitive to erythromycin.
Most gram-negatives are resistant to erythromycin due to its inability
to penetrate the lipopolysaccharide- cell wall complex.
Not indicated as an adjunct in the treatment of periodontitis due to the
incidence of gram-negative anaerobes associated with such sites and
the failure of the drug to achieve therapeutic levels in the gingival
crevicular fluid
46
47. AZITHROMYCIN
Active against gram-negative anaerobes and provides higher
drug concentrations in the tissues than in blood or serum.
Therapeutic levels - require a single 250-mg dosage per day for 5
days following an initial loading dose of 500 mg
erythromycin which is usually given as 250 mg, 4 times daily, for
10-14 days
Highly effective against all serotypes of Actinobacillus
actinomycetemcomitans and against Porphyromonas
gingiualis
Erythromycin and azithromycin are both bacteriostatic and
interfere with bacterial protein synthesis by binding to the 50s
ribosomal subunit.
47
48. ADVERSE REACTIONS
Relatively nontoxic
Gastrointestinal symptoms such as nausea, vomiting, abdominal pain
and diarrhea are fairly common with oral preparations, but these are
rarely severe
Skin rashes, although rare, may occur as an allergic reaction to either
drug.
Extremely rare, more severe side effects may include heart palpitations
and chest pain, dizziness, headache, vertigo, vaginitis and nephritis.
Both drugs are excreted in human breast milk, and caution should be
exercised when either drug is administered to a nursing mother.
The safety and effectiveness of azithromycin for the treatment of
children or adolescents under the age of 16 years has not been
established
48
49. DRUG INTERACTION
Usage of erythromycin with - theophylline, oral anticoagulants
or digoxin -result in elevated serum levels - lead to toxicity.
Increased anticoagulant effects when erythromycin and oral
anticoagulants are used together.
Patients receiving carbamazepine, cyclosporine, hexobarbital or
phenytoin may result in elevated serum levels of erythromycin.
Antacids containing either aluminum or magnesium have been h
known to reduce the peak serum levels obtained with
azithromycin.
Because they have similar modes of action, neither erythromycin
nor azithromycin should be given concurrently with clindamycin
49
50. CLINDAMYCIN
Is a lincosamide antibiotics similar in mechanism of actionand spectrum of
activity with erythromycin.
Inhibits bacterial protein synthesis by binding to the 50s ribosomal subunit.
Due to competition for the same binding site, the two drugs are antagonistic
and should not be administered together.
Active against most gram-positive bacteria, including both facultative and
anaerobic species, but most gram negative aerobic bacteria are resistant.
50
51. Active against almost all gram-negative anaerobes, including those
associated with the oral cavity and the periodontal pocket.
Tetracyclines, penicillins and erythromycin are much less active
Adjunctive use of clindamycin hydrochloride has been found to be
effective in the treatment of refractory periodontitis that has not
responded to tetracycline
Clindamycin penetrates well into the gingival fluid and maintains
concentrations in excess of the minimum inhibitory concentrations for
most bacteria associated with adult periodontitis
Eikenella corrodens - resistant to the drug
Clindamycin is not indicated in the treatment of aggressive
periodontitis due to the in vitro resistance encountered with
A.actinomycetemcomitans.
51
52. Adverse reactions
Diarrhea, abdominal cramps, esophagitis and stomach irritation are
well-recognized side effects associated with the oral administration of
clindamycin hydrochloride and are relatively common
Diarrhea may occasionally be severe and persist for 1 or 2 weeks after
the drug is stopped
Generalized mild to moderate skin rashes may occur in approximately
10% of the patients due to hypersensitivity to clindamycin.
Anaphylactoid reactions are extremely rare.
Numerous reports of pseudomembranous colitis associated with
parenteral administration of clindamycin
Because of the potentially serious adverse effects associated with
clindamycin therapy, this drug should probably be reserved for
anaerobic infections that are not amenable to other forms of therapy.
52
53. DRUG INTERACTION
Have neuromuscular blocking properties and should not be
given with other neuromuscular blocking agents since it may
enhance the effect.
Clindamycin should not be given concurrently with either
erythromycin or azithromycin because of competition for the
same ribosomal binding site
53
54. INTERFERENCE WITH NUCLEIC ACID SYNTHESIS
Antimicrobial agents preferentially inhibit either DNA
or RNA synthesis.
Unfortunately, very few of these are of clinical use in
the treatment of bacterial infections since most do not
exhibit selective toxicity.
However, the rifamycins, nitroimidazoles and
quinolones do exhibit selectivity toxicity and are
clinically useful in the treatment of certain bacterial
infections.
54
55. RIFAMYCINS
The rifamycins were initially discovered in 1957 and were found
to possess good activity
gram-positive
gram-negative
exceptional activity against Mycobacterium tuberculosis
Chemical modifications of the basic structure resulted in
rifampicin.
absorbed after oral administration
prolonged antibacterial level in the blood
greater activity against mycobacteria and other bacteria.
The drug is exceptional in its selective inhibition of RNA
synthesis in bacteria, since it has little or no effect on either
mammalian DNA or RNA synthesis.
55
56. Mechanism of action
Specific binding bacterial DNA dependent RNA polymerase
DNA transcription .
Although mammalian cells contain RNA polymerase, these enzymes
are much less sensitive to the effects of rifampicin due to the
differences in their structure.
56
57. NITROIMIDAZOLES
Metronidazole, tinidazole, ornidazole, satranidazole
METRONIDAZOLE
Metronidazole was initially introduced in the 1960s as a treatment for
trichomonal vaginitis.
Beneficial effect on acute ulcerative gingivitis.
Primary use - obligate anaerobic bacteria associated with the oral cavity
and the intestinal and female genital tracts.
Oral administration of metronidazole with either amoxicillin or
Augmentin.
The combination of metronidazole and amoxicillin has been reported
to be particularly effective in the treatment of A.
actinomycetemcornitans- associated periodontitis
57
59. 59
Adverse Reactions
12% of the patients experiencing nausea accompanied by headache,
anorexia and vomiting.
Unpleasant metallic taste
Drowsiness, headache, depression, skin rashes and vaginal and
urethral burning.
Metronidazole affects the activity of hepatic enzymes involved with the
metabolism of ethanol and acetaldehyde
Taken with alcohol, it produces unpleasant symptoms due to the
accumulation of acetaldehyde in the blood.
Most severe reactions have been convulsive seizures and peripheral
neuropathy.
Should not be given to pregnant women or nursing mothers.
60. DRUG INTERACTION
Alcoholic beverages - abdominal cramps, nausea, vomiting,
headaches and flushing may occur
Toxic psychosis - alcoholics receiving disulfiram, an anti-
abuse drug.
Metronidazole has been reported to potentiate the
anticoagulant effect of warfarin and other oral coumarin
anticoagulants and should not be given concurrently.
Patients stabilized on relatively high doses of lithium-
elevated serum lithium levels and the possibility of lithium
toxicity.
60
61. QUINOLONES
Constitute a group of 1,8-naphthyridine derivatives.
Synthetically produced drugs and therefore are not true
antibiotics since they are not the byproduct of microorganisms.
Nalidixic acid was introduced into clinical use in 1964 and is the
prototype of the quinolone drugs.
Improved antibacterial spectrum have been synthesized -
chemically similar.
Divided
Older quinolones
Newer generation quinolones – I and II
61
62. First generation
Norfloxacin, ciprofloxacin, ofloxacin, pefloxacin.
Second generation
Lomefloxacin, moxifloxacin, levofloxacin,sparfloxacin
They are compounds with additional fluoro and other
substitutions.
Increased antimicrobial activity to gram+ cocci and anaerobes
and longer half life.
Naladixic acid and ciprofloxacin – bactericidal
Bactericidal effect can only occur in the presence of competent
RNA and protein synthesis
62
63. CIPROFLOXACIN
Ciprofloxacin is the first oral broad-spectrum antimicrobial agent with
good activity .
Excellent activity against a wide range of gram-negative organisms,
including many that are resistant to third-generation cephalosporins,
broad-spectrum penicillins and the newer semisynthetic
aminoglycosides.
Good activity against gram-positive bacteria and is thus particularly
useful in the management of mixed infections.
Although the newer quinolones may not be used routinely by the
dental professional due to resistance encountered with the oral flora.
Ciprofloxacin reportedly does not cross-react with most antibiotics
63
64. ADVERSE EFFECTS
Nausea, headache, abdominal discomfort or epigastric
upset.
Photosensitivity to light has been reported manifested as
exaggerated sunburn.
Dizziness and lightheadedness may occur and patients
should be informed to avoid driving or operating
machinery while taking the drug.
It should not be given to nursing mothers or pregnant
women except in the case of severe infections.
Not recommended for use in prepubertal children.
64
65. DRUG INTERACTION
Toxicity may occur due to the inhibitory effect of ciprofloxacin
on theophylline if given together.
Concurrent administration with antiacids containing
magnesium, aluminum, calcium, zinc-containing multivitamins
or iron-containing preparations may substantially interfere with
the absorption of ciprofloxacin.
Quinolones have been reported to enhance the effect of warfarin
and other oral anticoagulants.
65
68. PARADOXICAL” OR “EAGLE” EFFECT
Increasing the concentration of the penicillins greater than 4-5 times
the minimal inhibitory concentration does not result in greater
microbial killing and may even result in a effect whereby very high
beta-lactam concentrations result in a reduced rate of microbial killing.
POSTANTIBIOTIC EFFECT
The postantibiotic effect concerns the persistent suppression of
bacterial growth after previous exposure to an antibiotic agent
Varies
type of antibiotic agent,
drug concentration,
duration of therapy and
microorganism targeted
68
69. Antibiotics acting intracellularly by affecting ribosomal protein
synthesis (erythromycin, tetracyclines or clindamycin) or nucleic
acid (DNA) synthesis (quinolones or metronidazole).
Erythromycin and tetracycline 5-10 hrs – streptococcus
pneumonia and pyogens
Aminoglycosides 2-7 hrs – E.coli, klebsiella pneumoniae
Clinical significance of the postantibiotic effect remains
unknown
Agents with significant postantibiotic effects can probably be
given at less frequent dosing intervals
69
70. DURATION OF ANTIBIOTIC THERAPY
A significant misconception - “complete course” of therapy.
Faulty assumptions: Prolonged antimicrobial therapy destroys
resistant microorganisms.
Prolonged antibiotic therapy is necessary for “rebound” infections
that recur since the organisms are suppressed but not eliminated.
The ideal duration of antibiotic therapy is the shortest that will
prevent both clinical and microbiological relapse.
There is limited information on the proper dosage, dosing interval
or dosing duration for the antimicrobial management of
periodontopathic microorganisms.
70
71. SEQUENCING OF ANTIBIOTIC THERAPY
Use of potent antibiotics without thorough mechanical debridement
and without adequate clinical diagnosis, microbiological analysis and
susceptibility testing of target organisms should be regarded as
improper
71
Initial periodontal therapy
Broad-spectrum antiseptic agents
Clinical response is evaluated
Microbiological examination of subgingival microbiota
Presence and the level of remaining putative periodontal pathogens
(After 1-3 months)
72. 72
Susceptibility testing
(After 1-3 months)
Microbiological examination of subgingival microbiota
Elimination of target pathogens and screen for possible superinfecting organisms.
High levels of viridans streptococci and Actinomyces species
suggestive of periodontal health or minimal disease
maintenance care program
Screening for and eradication of exogenous pathogens (A.acomitans and P gingivalis)
73. SPECIFIC CONSIDERATIONS
Two critical factors
Gingival fluid concentration
Minimum inhibitory concentration (MIC).
The gingival fluid concentration (CGCF) provides information on
the peak levels achieved by systemic delivery at the primary
ecological niche for periodontal pathogens, the periodontal
pocket.
The 90% minimum inhibitory concentration (MIC90) is an in
vitro determination of the concentration that will inhibit growth
of 90% of the bacterial strains of a species that are tested.
Antimicrobial activity can be defined as a relationship between
CGCF and MIC90
100 (CGCF/MIC90) = antimicrobial activity expressed as a
percentage for each antibiotic and each organism.
73
74. Periodontal diseases in which antibiotics can be used:
Chronic periodontitis: patients not responding to
periodontal therapy (refractory periodontitis) and
patients with recurrent disease.
Tetracycline,
Doxycycline,
Metronidazole,
Clindamycin,
Amoxicillin + Clavulinic acid (Augmentin),
Azithromycin,
Metronidazole + Amoxicillin,
Spiramycin.
74
75. Aggressive periodontitis: Localized aggressive
periodontitis (LAP) mostly
involvingAggregatibacteractinomycetemcomitan scan
be controlled or eradicated by systemic
metronidazole-amoxicillin combination therapy.
Other antibiotics recommended for both localized and
generalized aggressive periodontitis are:
Tetracycline,
Doxycycline,
Minocycline,
Metronidazole,
Amoxicillin + Clavulinic acid (Augmentin),
75
77. Necrotizing periodontal diseases: Patients with
moderate or severe NUG or necrotizing ulcerative
periodontitis (NUP), local lymphadenopathy and
systemic involvement need antibiotic therapy.
Antibiotics recommended are
amoxicillin,
metronidazole
combination of amoxicillin+metronidazole.
77
78. Periodontal abscess: Antibiotic therapy is indicated for
periodontal abscesses with systemic manifestations (fever,
malaise, lymphadenopathy). Antibiotics for the treatment
of abscesses should be prescribed in conjunction with
surgical incision and drainage.
Amoxicillin: Loading dose of 1.0 g followed by a
maintenance dose of 500 mg/t.i.d. for 3 days,
followed by a patient evaluation to determine whether
further antibiotic therapy or dosage adjustment is required.
With allergy to ß-lactam drugs:
Clindamycin: Loading dose of 600 mg on day 1, followed by
300 mg/q.i.d. for 3 days.
78
79. COMBINATION AND SERIAL THERAPY
Since the subgingival microbiota in destructive periodontal
disease consists of various putative pathogens that may differ in
antimicrobial susceptibility, the use of a combination of two or
more antibiotics may represent a valuable approach in
periodontal chemotherapy.
ADVANTAGES
To broaden the antimicrobial range of the therapeutic regimen
beyond that attained by any single antibiotic;
To prevent or forestall the emergence of bacterial resistance by
using agents with overlapping antimicrobial spectra; and
To lower the dose of individual antibiotics by exploiting possible
synergy between two drugs against targeted organisms.
79
80. DISADVANTAGES
Increased adverse reactions;
Antagonistic drug interactions with improperly selected
antibiotics. A bactericidal antibiotic (B-lactam drugs or
metronidazole) should not be used simultaneously with
a bacteriostatic agent (tetracyclines) because the
bactericidal agent exerts activity during cell division that
is impaired by the bacteriostatic drug.
80
82. ANTIBIOTICS PROPHYLAXIS IN MEDICALLY
COMPROMISED PATIENTS
Antibiotic prophylaxis involves the administration of
antibiotics to patients with no evidence of current
infection to prevent post-treatment microbial
colonization and complications
82
83. PRINCIPLES OF ANTIBIOTIC PROPHYLAXIS
1) the benefit of the prophylaxis must outweigh the risk of taking the
antibiotic (satisfactory risk-benefit ratio).
2) the antibiotic must be present in the blood and target tissues prior to
dissemination of the organisms into the blood .
3) an antibiotic loading dose must be used .
4) the choice of the antibiotic must be made on the basis of the single
most likely microorganism to cause the infection .
5) the antibiotic should be continued only as long as microbial
contamination from the operative site continues .
6) the financial costs of the antibiotic prophylaxis must be reasonably
related to the risk of acquiring the infection and the costs of treating
this infection and possible sequelae (a satisfactory cost-benefit ratio).
83
84. MEDICAL HARM
1) an increased risk of antibiotic- induced allergy and toxicity
(if no antibiotic prophylaxis is used, the drug-related
adverse effects are zero),
2) an increased risk of superinfection (initiation of a new
infection while treating a primary infection),
3) selection of antibiotic-resistant microorganisms (damage
to the host and environmental microbial ecology),
4) encouragement of careless, inept surgery
84
86. In the 1930s it became clear that dental treatment may
induce bacteremia, with potential to produce distant
infections such as infective endocarditis.
86
88. RESISTANCE TO ANTIBIOTICS
Due to the widespread use of antibiotics in our society, antibiotic
resistance is a serious medical, economic and public health problem.
This is particularly true in the practice of periodontics, since there has
been a growing trend over the past decade in the adjunctive use of
antibiotics in the treatment of destructive periodontal diseases.
88
90. Low-level penicillin resistance in certain
microorganisms such as the pneumococci is thought
to be due to mutations that result in changes in the
penicillin-binding proteins . Increases in resistance to
several other antibiotics also occur by mutations that
result in changes in the proteins associated with the
permeability of the outer membrane of the bacterial
cell.
90
92. A time when antibiotic resistance is increasing researchers have
found that lactic acid bacteria(LAB) found in fresh honey could
possibly offer alternative to antibiotics.
T C Olofsson et al
Lactic acid bacterial symbionts in honeybees- an unknonwn key
to honey’s antimicrobial and therapeutic activites Int Wound J
2014;10:1-12
Lab tested against severe wound pathogens such as methicillin-
resisitant staphylococcus aureus, vancomycin- resisitant
enterococcus and psuedomonas aeruginosa.
Strong antimicrobial activity fromeach symbiont and a
synergestic effect, which counteracted all the tested pathogens
92
RECENT ADVANCES
93. CONCLUSION
Systemic periodontal antibiotic therapy aims to reinforce
mechanical periodontal treatment and to support the host
defense system in overcoming the infection by killing
subgingival pathogens that remain after conventional
mechanical periodontal therapy.
Single antimicrobial drug therapies are able to suppress the
number of subgingival indigenous bacteria for a prolonged
period of time depending on the host defense and oral
hygiene efforts. Combination drug therapies aim at
enlarging the antimicrobial spectrum and exploiting
synergy between antibiotics and may be indicated with
complex mixed subgingival infections
93
94. REFERENCES
K.D. Tripathi Essentials of pharmacology
Carranza's clinical periodontology 9th edition; ch 50: 675-687
Jan Lindhe Clinical Periodontology and Implantology 5th edition; ch
42 : 882-897
Hall's Critical decisions in periodontology 4th edition; ch 51 : 102-104
Pharmacokinetic principles of antimicrobial therapy Periodontology
2000, Vol. 10; 1996: 5-11
Selected antimicrobial agents: mechanisms of action, side effects and
drug interactions Periodontology 2000, Vol 10; 1996 :29-44
Systemic anitbiotic therapy in periodontics Periodontology 2000, Vol.
10; 1996: 45-78
94
95. The acquisition of antibiotic resistake in the periodontal
microflora Periodontology 2000, Vol. 10; 1996: 79-88
Antibiotic prophylaxis and the medically compromised patient
Periodontology 2000, Vol. 10; 1996: 107-138
Antibiotic toxicity, interactions and resistance development
Periodontology 2000, Vol. 28;2002: 280–297
Position Paper Systemic Antibiotics in Periodontics J Periodontol
2004;75:1553-1565.
Systemic antibiotic therapy in periodontics Dent Res J 2012 Sep-
Oct; 9(5): 505–515
Advances in periodontal drug delivery systems Int. J. Novel Drug
Deliv. Tech. Jan-Mar 2012 ;Vol-2 :
95
There are numerous antibiotics that could be employed to treat periodontal infections, but it is often unclear which antibiotic would provide the greatest benefi t to a patient with a specifi c periodontal infection, with minimal adverse effects.
Microscopic studies from the turn of the century revealed large numbers of spirochetes and amoebae in subgingival plaque. These microorganisms were considered the cause of periodontal disease (“pyorrhoea”) and treated with neo-salvarsan or ementin. inorganic arsenic compounds were associated with considerable adverse reactions, proving true the old saying “Graviora quaedum sunt rernedia periculus” (some remedies are worse than the disease). The next major chemotherapeutic agent to be developed from a synthetic dye was prontosil, a compound converted in the human body to sulfonamide. Sulfonamides and related compounds are still used in antimicrobial therapy. The greatest discovery in the era of antibiotics was Fleming’s finding of Penicillium notatum producing a substance (“penicillins”) that inhibited the growth of Staphylococcus aureus
Tetracycline- HC1 became popular in the 1970s due to its broadspectrum antimicrobial activity and low toxicity
The prime candidates for systemic antimicrobial therapy are those patients exhibiting attachment loss after seemingly adequate conventional therapy, or patients with aggressive forms of periodontitis or associated with predisposing medical conditions or refractory periodontitis.
Patients with acute or severe periodontal infections (periodontal abscess, acute necrotizing gingivitis/periodontitis) may also benefit from antibiotic therapy
Evidence indicates that the penicillins and cephalosporins interfere with the transpeptidation reaction by acting as a steric analog of the malanine- D-alanine portion of the pentipeptide chain on the N-acetyl muramic moiety. The chemical groupings around the B -lactam ring are similar in structure to the terminal end of the pentapeptide on the newly synthesized peptidoglycan subunit. Because of this similarity, the enzymes involved in the transpeptidation reaction react with the B-lactam nucleus. . Afterbinding to one of these enzymes, the reactive B-lactam ring opens and covalently attaches the B-lactam molecule to the enzyme. The binding of the B-lactam antibiotic inactivates the transpeptidase reaction and results in the formation of new peptidoglycan chains that are not cross-linked and lack tensile strength. Weak points develop in the growing cell wall, which results in cell rupture due to osmotic lysis.
misreading of the mRNA and consequently results in the incorporation of the wrong amino acids into the growing peptide chain and the production of faulty proteins. However, this alteration may be small and may not effect all proteins. This alone does not account for the bactericidal effect of the aminoglycosides. Evidence indicates that the bactericidal effect of these drugs may be due to their ability to cause detachment of the ribosomal complex from the mRNA, which would result in the inability of the cell to produce essential proteins
The drugs bind principally to the 30s ribosomal subunit and specifically inhibit the binding of aminoacyl-t-RNA to the ribosomal acceptor site. In high concentrations, they may cause alterations in the cytoplasmic membrane, which results in leakage of nucleotides and other compounds from the cell. This action probably accounts for the rapid inhibition of DNA replication, which occurs at the site of the membrane, when cells are exposed to high concentrations of tetracycline. In higher concentrations, tetracyclines may also inhibit protein synthesis in mammalian cells.
Rifampicin is inhibitory for fungi when given with amphotericin B, which acts on the fungi membrane, allowing rifampicin to penetrate the cell. Rifampicin is also antiviral and inhibits both DNA-dependent RNA polymerases (transcriptases) and RNA dependent DNA polymerases (reverse transcriptases) in the poxviruses and adenoviruses
. Rifampicin is extremely potent as an antistaphylococcal drug, but its use alone results in the rapid emergence of rifampicin-resistant mutants. Rifampicin- resistant mutants also occur rapidly in other bacteria, with the possible exception of M. tuberculosis, when the drug is used alone.
Metronidazole, a 5-nitroimidazole compound, specifically targets anaerobic microorganisms but has essentially no activity against aerobic or microaerophilic
bacteria. Initially, metronidazole was thought to interact with biochemical pathways present only in obligate anaerobes. It is now known that cytotoxic metabolites of metronidazole directly interact with bacterial DNA, and possibly other macromolecules, resulting in cell death. Upon entry into an anaerobic organism, metronidazole is reduced at the 5-nitro position by electron transport proteins that are part of anaerobic metabolic energy-yielding pathways. Alteration of the metronidazole molecule creates a continuous concentration gradient favoring diffusion of additional metronidazole into the cell. Reduction of the parent compound yields many short-lived cytotoxic free radicals
Eagle effect, Eagle phenomenon, or paradoxical zone phenomenon, named after Harry Eagle who first described it, originally referred to the paradoxically reduced antibacterial effect of penicillin at high doses, though recent usage generally refers to the relative lack of efficacy of beta lactam antibacterial drugs on infections having large numbers of bacteria. Proposed mechanisms:
Reduced expression of penicillin binding proteins during stationary growth phase.
A postantibiotic effect is more persistent with antibiotics acting intracellularly by affecting ribosomal protein synthesis (erythromycin, tetracyclines or clindamycin) or nucleic acid (DNA) synthesis (quinolones or metronidazole). The beta-lactams and vancomycin only have a significant postantibiotic effect against Staphylococcus aureus; erythromycin and tetracycline may maximally show a 5- to 10-hour postantibiotic effect against Streptococcus pyogenes and Streptococcus pneumoniae; and aminoglycosides may demonstrate a 2- to 7-hour postantibiotic effect against Escherichia coli, Klebsiella pneumoniae and Pseudomonasaeruginosa. The postantibiotic effect renders microorganisms more susceptible to the action of leukocytes or postantibiotic leukocyte enhancement
Induction of microbial resistance mechanisms (such as beta lactamases with short half-lives) by high drug concentrations[5]
Precipitation of antimicrobial drug in vitro,[1] possibly also leading to the crystallized drug being mis-detected as colonies of the microbe.
Self-antagonising the receptor with which it binds (penicillin binding proteins, for example, in the case of a penicillin).[6]
Penicillin is a bactericidal antibiotic that works by inhibiting cell wall synthesis but this synthesis only occurs when bacteria are actively replicating (or in the log phase of growth). In cases of extremely high bacterial burden (such as with Group A Strep), bacteria may be in the stationary phase of growth. In this instance since no bacteria are actively replicating (presumably due to nutrient restriction) penicillin has no activity. This is why adding an antibiotic like clindamycin, which acts ribosomally, kills some of the bacterial and returns them to the log phase of growth
Intrinsic resistance refers to an inherent resistance that is a naturally occurring trait of the organism and as such may be considered a species characteristic.
. Transformation is the process by which bacteria acquire segments of free DNA from the surrounding environment. This process is frequently used in the laboratory to insert DNA from one bacterium into another bacteria such as the pneumococci and the gonococci possess a natural transformation system that facilitates the entry of exogenous DNA into the cell. . In addition to the preparation of recipient cells capable of taking up the exogenous DNA, it is often necessary to purify the exogenous donor DNA to prevent it from degrading by DNASE
b A second mechanism for the transfer of DNA from a donor to a recipient bacterium involves a phenomenon referred to as transduction. This is a process by which exogenous DNA is transferred from one bacteriumto another by insertion in a phage particle. The source of the DNA may be from a plasmid within the bacterial cell or it may involve a portion of the bacterial chromosome. In transduction, the bacterial cell is infected by the phage .
The best example of resistance genes transferred by this mechanism are the p-lactamase and heavy metal resistance plasmids of staphylococci. These plasmids are packaged by the phage and carried from one cell to another
The most common mechanism of transfer of antibiotic resistance genes is by conjugation.
This process requires cell-to-cell contact and involves the transfer of plasmid DNA from a donor bacterium to a recipient bacteria. Plasmids are small extrachromosomal elements of DNA that can be easily exchanged between different bacteria of the same species or even between bacteria of different species